Non-specific X-linked mental retardation is a common term used to describe a heterogenous subgroup of male mental retardates which probably accounts for 25% of the retarded population. In some families with this disorder, the affected males exhibit a "marker X" chromosome with a fragile site at band q27 (fragile Xq) and usually macro-orchidism. Between 4 and 7% of mildly retarded females may also have a fragile Xq. In males, the fragile Xq expression is variable and is dependent on the culturing conditions (including folic acid and methionine concentration) used for lymphocyte culture. The specific aims of this proposal are population screening for the fragile Xq (diagnosis), linkage studies with G-6-PD and the Xg blood group (gene location on the X), culturing studies to look at biochemical effects on fragile Xq expression and frequency, folate studies to examine folate coenzymes in lymphocytes and effects of sex hormones on the fragile Xq and folate coenzymes, studies on carrier females and fibroblast lines and culture screening for autosomal fragile sites. Screening for macro-orchidism will be done in a large population of retarded males with cytogenetic screening on those over the 90th percentile; a group of mildly retarded females will be screening directly for the fragile Xq as will a group of vocational rehabilitation students and other referrals. Follow-up testing (cytogenetic, biochemical, structural) and counseling will be available for all positives and their families. Culturing studies seek to increase fragile Xq expression and define the underlying biochemical requirements for such expression, especially the requirement for methionine. Any generated data will be applied to cells from carrier females and fibroblast lines to attempt to increase fragile Xq expression allowing more reliable testing and risk assessment for carrier females and, ultimately, prenatal detection (by amniocentesis) for affected males.